Traditional cancer chemotherapy has primarily been based on highly cytotoxic drugs that nonspecifically target any dividing cell, thereby inducing global systemic toxicity with only a modest improvement in patient survival. Indeed, cancer is still the second leading cause of mortality in the United States, with 1,444,920 new cases and 559,650 deaths in 2007. There is clearly an urgent need for a new paradigm in the management of cancer. The goal of this project is to engineer a next generation nanoparticle that can deploy a combination of a signal transduction inhibitor of an aberrant oncogenic pathway along with a cytotoxic chemotherapeutic agent to exert a superior antitumor outcome with reduced adverse effects. Specifically, we will engineer a multifunctional nanoparticle that can inhibit the mitogen activated protein kinase (MAPK) pathway, a critical oncogenic pathway, and additionally deliver doxorubicin after homing into the tumor. The specific aims are: Aim 1: To engineer a tumor 'targeted' multifunctional nanoparticle from a defined ratio of polylactide polyglycolide (PLGA)-doxorubicin and PLGA-PD98059, a MAPK (MEK) inhibitor. Additionally, we will integrate a targeting peptide to the nanoparticle, which has already been optimized for targeting nanoparticles to tumors, to test the hypothesis that 'targeted' nanoparticles result in superior antitumor outcome as compared to homing by enhanced permeability and retention (EPR) effect. Aim 2: To test the efficacy of the multifunctional nanoparticle in vitro and in vivo. We have identified cancer cell lines that exhibit activated MAPK status, and are susceptible or resistant to doxorubicin, which would serve as powerful tools to test and optimize the multifunctional nanoparticles. Furthermore, we have established a luciferase-expressing RAS-activated ovarian mouse transgenic cancer model, a 4T1 breast cancer model and a B16/F10 melanoma syngeneic model with activated MAPK signaling, which will be used in this study. Aim 3. To elucidate the mechanisms underlying the activity of the multifunctional nanoparticle. At a tissue level, we will test the tissue distribution of the nanoparticles with the anticipation that enhanced delivery to the tumor could be the mechanism underlying improved therapeutic index. At a molecular level, we will dissect the effect of treatment on the phosphorylation status of ERK, and its correlation with cell proliferation index, apoptosis and tumor angiogenesis. We anticipate that achieving these goals will enable the development of a mechanistically-inspired multifunctional nanoparticle for the treatment of cancers driven by the MAPK signaling pathway. Additionally, it will shed insights into the rational combination of two active agents in a nanoparticle, thereby opening up the possibility of engineering next generation nanoparticles.